US6147103A - Omeprazole process and compositions thereof - Google Patents
Omeprazole process and compositions thereof Download PDFInfo
- Publication number
- US6147103A US6147103A US09/387,945 US38794599A US6147103A US 6147103 A US6147103 A US 6147103A US 38794599 A US38794599 A US 38794599A US 6147103 A US6147103 A US 6147103A
- Authority
- US
- United States
- Prior art keywords
- omeprazole
- residual
- solution
- mcpba
- methylene chloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 title claims abstract description 54
- 229960000381 omeprazole Drugs 0.000 title claims abstract description 52
- 239000000203 mixture Substances 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title abstract description 32
- 230000008569 process Effects 0.000 title abstract description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 73
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 69
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- 239000002904 solvent Substances 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 5
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims 2
- 125000003944 tolyl group Chemical group 0.000 claims 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 abstract description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 21
- 230000001476 alcoholic effect Effects 0.000 abstract description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 abstract description 18
- 238000002425 crystallisation Methods 0.000 abstract description 17
- 230000008025 crystallization Effects 0.000 abstract description 17
- XURCIPRUUASYLR-UHFFFAOYSA-N Omeprazole sulfide Chemical compound N=1C2=CC(OC)=CC=C2NC=1SCC1=NC=C(C)C(OC)=C1C XURCIPRUUASYLR-UHFFFAOYSA-N 0.000 abstract description 15
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 15
- 238000006053 organic reaction Methods 0.000 abstract description 15
- 239000000047 product Substances 0.000 abstract description 15
- 239000012043 crude product Substances 0.000 abstract description 10
- 238000002360 preparation method Methods 0.000 abstract description 10
- 238000000746 purification Methods 0.000 abstract description 9
- 238000002955 isolation Methods 0.000 abstract description 8
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 abstract description 8
- 238000010899 nucleation Methods 0.000 abstract description 8
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 abstract description 4
- 238000005292 vacuum distillation Methods 0.000 abstract description 4
- 238000001035 drying Methods 0.000 abstract description 3
- -1 alkyl formate Chemical compound 0.000 abstract description 2
- 239000003699 antiulcer agent Substances 0.000 abstract description 2
- 238000001914 filtration Methods 0.000 abstract description 2
- 239000003960 organic solvent Substances 0.000 abstract description 2
- 238000001953 recrystallisation Methods 0.000 abstract description 2
- 239000002243 precursor Substances 0.000 abstract 1
- 238000005406 washing Methods 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 46
- 239000000243 solution Substances 0.000 description 32
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 22
- 238000007254 oxidation reaction Methods 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 18
- FVVXWRGARUACNW-UHFFFAOYSA-N 3-methylisoquinoline Chemical compound C1=CC=C2C=NC(C)=CC2=C1 FVVXWRGARUACNW-UHFFFAOYSA-N 0.000 description 17
- 239000007800 oxidant agent Substances 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- 230000003647 oxidation Effects 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 9
- DTBDAFLSBDGPEA-UHFFFAOYSA-N 3-Methylquinoline Natural products C1=CC=CC2=CC(C)=CN=C21 DTBDAFLSBDGPEA-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- 239000012535 impurity Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 230000001590 oxidative effect Effects 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 150000003457 sulfones Chemical class 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 150000001204 N-oxides Chemical class 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
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- 238000000576 coating method Methods 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
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- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000006911 nucleation Effects 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
- 239000011736 potassium bicarbonate Substances 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- BTEXQKZNRLDUMG-UHFFFAOYSA-N 3-methyl-2-oxidoisoquinolin-2-ium Chemical compound C1=CC=C2C=[N+]([O-])C(C)=CC2=C1 BTEXQKZNRLDUMG-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical class O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 229920000945 Amylopectin Chemical class 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Chemical class OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical class OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical class OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 229930195725 Mannitol Chemical class 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Chemical class 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical class O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229920002678 cellulose Chemical class 0.000 description 2
- 239000001913 cellulose Chemical class 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 235000013681 dietary sucrose Nutrition 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- USSBDBZGEDUBHE-UHFFFAOYSA-L magnesium;2-oxidooxycarbonylbenzoate Chemical compound [Mg+2].[O-]OC(=O)C1=CC=CC=C1C([O-])=O USSBDBZGEDUBHE-UHFFFAOYSA-L 0.000 description 2
- 239000000594 mannitol Chemical class 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000612 proton pump inhibitor Substances 0.000 description 2
- 239000013557 residual solvent Substances 0.000 description 2
- 238000004007 reversed phase HPLC Methods 0.000 description 2
- 239000000600 sorbitol Chemical class 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 229920002261 Corn starch Chemical class 0.000 description 1
- 208000007882 Gastritis Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 238000010268 HPLC based assay Methods 0.000 description 1
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- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 description 1
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 239000003831 antifriction material Substances 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
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- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 206010013864 duodenitis Diseases 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
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- 230000014759 maintenance of location Effects 0.000 description 1
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- 230000007246 mechanism Effects 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
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- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001592 potato starch Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940089505 prilosec Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
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- 229910001220 stainless steel Inorganic materials 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
Definitions
- the present invention provides a novel improved process for the preparation, isolation, and purification of the anti-ulcer agent omeprazole.
- Compositions of omeprazole containing no chromatographically detectable levels of residual non-alcoholic organic reaction solvent are also disclosed.
- Omeprazole the generic name for 5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (denoted as Formula I below) is a well-described gastric proton-pump inhibitor and is on the market as LOSEC® or PRILOSEC® for the treatment of gastric and duodenal ulcers, gastritis, duodenitis, and reflux esophagitis (see Merck Index, 12th Ed., entry 6977, and references cited therein).
- Omeprazole is commercially prepared via a multi-step sequence, the last step of which is oxidation of the sulfide intermediate, 5-methoxy-2-[[4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]methylthio]-1H-benzimidazole (denoted as Formula II below), known generically as pyrmetazole, which is typically effected with a peroxy acid, such as meta-chloroperoxybenzoic acid (hereinafter referred to as MCPBA) (U.S. Pat. Nos. 4,255,431 and 5,386,032), magnesium monoperoxyphthalate (MMPP) (U.S. Pat. No.
- MCPBA meta-chloroperoxybenzoic acid
- MCPBA meta-chloroperoxybenzoic acid
- MMPP magnesium monoperoxyphthalate
- suitable non-alcoholic organic reaction solvents include aromatic hydrocarbon solvents, such as benzene and toluene, and chlorinated aliphatic hydrocarbon solvents, such as chloroform and methylene chloride, in admixture with an alcoholic solvent, such as methanol, ethanol, isopropanol, or 1-butanol.
- suitable non-alcoholic organic reaction solvents are usually methylene chloride and toluene, and the preferred alcoholic solvent is ethanol.
- pyrmetazole contains two tertiary amino groups which can compete with the sulfide group for the oxidizing agent. Although these amino groups are less reactive than the desired sulfide, they can nevertheless undergo quantitative oxidation with MCPBA below ambient temperature.
- the product omeprazole (a sulfoxide) can also react with MCPBA to form a sulfone by-product.
- Non-chemoselectivity and over-oxidation characteristic of the previous methods, arise from ineffective control over the amount of the oxidizing agent as well as the manner in which the oxidizing agent is charged into the reaction vessel.
- Prior methods do not use accurately determined amounts of the oxidizing agent and do not provide for careful control of its addition to the reaction mixture.
- Non-chemoselective, over-, and under-oxidation all contribute to high impurities and loss of yield of the final desired product.
- a further drawback concerns diminished product quality resulting from occlusion of residual solvents and reaction by-products during the crystallization steps. It is desirable to eliminate residual levels of organic reaction solvent and recrystallization solvent impurities in the final crystalline product for toxicity/safety reasons.
- compositions of omeprazole having lower levels of residual non-alcoholic organic reaction solvent after the initial crude reactive crystallization step.
- the present invention provides an improved process for the preparation, purification, and isolation of omeprazole of the Formula I.
- the oxidizing agent is meta-chloroperoxybenzoic acid (MCPBA)
- the non-alcoholic organic reaction solvent is methylene chloride or toluene in admixture with an alcoholic solvent, such as methanol, ethanol, isopropanol, or 1-butanol, in particular, ethanol.
- MCPBA meta-chloroperoxybenzoic acid
- the completeness and chemoselectivity of the oxidation have been optimized by careful control of the amount of MCPBA charged to the reaction vessel.
- the use of one molar equivalent of MCPBA relative to the number of moles of pyrmetazole prevents non-chemoselective, over-, and under-oxidation resulting in fewer impurities and higher yields.
- the concentration of MCPBA in the charging solution is calculated using a novel analytical method based upon MCPBA oxidation of 3-methylisoquinoline to its N-oxide derivative and subsequent HPLC quantitation. Without this assay there exists no practical way to avoid either over-oxidation or incomplete conversion of pyrmetazole into omeprazole.
- control over localized over-oxidation is achieved by subsurface addition of MCPBA, providing for entry of the oxidizing solution into the reaction vessel at the tip of the agitator blades, with simultaneous control of the reaction temperature. Incorporation of these novel features into the process ensures complete conversion of pyrmetazole into omeprazole with no formation of sulfone by-products.
- the isolation of the crude product has been improved by vacuum distillation of the crude aqueous phase after extraction of the reaction mixture prior to crystallization to remove most of the entrained methylene chloride or toluene from the oxidation step.
- the alcoholic solvent, in particular ethanol, concentration is re-adjusted in order to promote good crystal growth during the crude crystallization step.
- the crystallization step involves a two-stage neutralization with a C 1-3 alkyl formate, preferably methyl formate, which is added subsurfacely through a diptube located near and directed perpendicular to the impeller tip. This mode of addition of the methyl formate ensures rapid dispersion of the neutralizing agent, which promotes crystal growth over spontaneous nucleation.
- a further embodiment of the present invention concerns the final purification step.
- a methanol-water mixture is used for the crystallization step which is initiated by subsurface addition of aqueous acetic acid and subsequent seeding with omeprazole.
- the same methanol-water mixture is employed as a displacement wash to remove mother liquors and dissolved impurities while suppressing solubility losses. In this fashion, significant yield improvements are obtained with no adverse impact on product quality.
- Crystalline omeprazole is thus obtained with significant improvement in yield and purity.
- the isolated material contains no chromatographically detectable levels of residual non-alcoholic organic reaction solvent and less than 20 p.p.m. of residual methanol as the crystallization solvent.
- the instant invention relates to an improved process for the preparation, purification, and isolation of the proton-pump inhibitor omeprazole and to novel compositions thereof.
- Omeprazole, having formula I is prepared by reacting a solution of pyrmetazole, having Formula II, cooled to about -5 to +5° C. and buffered to a pH of about 5 to 6, ##STR2## with one molar equivalent of an oxidizing agent, relative to the number of moles of pyrmetazole, dissolved in a non-alcoholic organic reaction solvent in admixture with an alcoholic solvent.
- the alcoholic solvent is selected from methanol, ethanol, isopropanol, and 1-butanol.
- the buffered solution comprises potassium bicarbonate
- the oxidizing agent is meta-chloroperoxybenzoic acid
- the non-alcoholic organic reaction solvent is methylene chloride or toluene, either in admixture with ethanol.
- MCPBA solid contains about 15-25% water for safety reasons, the solid is not homogeneous. Therefore, the manufacturer can provide only the average assay results of MCPBA. If MCPBA from different containers and different suppliers is used, an inaccurate charge of MCPBA will result.
- a novel analytical method has therefore been developed to quantify MCPBA in the charging solution in order to deliver an accurate amount of the oxidizing agent.
- an excess amount of 3-methylisoquinoline (III) is reacted with CPBA in toluene/ethanol solution to form 3-methylisoquinoline N-oxide (IV), according to the equation: ##STR3##
- the reaction is fast and quantitative.
- the remaining tertiary amine in the reaction mixture is quantitated by reverse-phase high-performance liquid chromatography (RP-HPLC). The amount of the amine consumed during the reaction is used to calculate the concentration of the MCPBA solution.
- Chemoselectivity and extent of oxidation are also enhanced by controlling the reaction temperature without crystallization of the oxidizing agent.
- the optimum temperature range is about 0-5° C. for the solution of the oxidizing agent and about -5 to +5° C. for the reaction mixture throughout the addition process. Higher temperatures of either the MCPBA solution or the reaction mixture will result in some sulfone formation. Likewise, much lower temperatures temporarily suppress the oxidation reaction, which results in a localized accumulation of the oxidizing a gent that can lead to over-oxidation products.
- aqueous base for example 50% NaOH or KOH
- the solution allowed to age for about 0.5-1.0 hours at 0-5° C., and the aqueous phase separated from the organic phase.
- the source of residual toluene or methylene chloride is an emulsion that forms when the crude batch is extracted from toluene or methylene chloride with aqueous base. Removal of residual solvent may be accomplished by vacuum distillation of the aqueous phase at a pressure of about 25-70 mm Hg and temperature of about 15-35° C. for about 1-4 hours. In further exemplification, the distillation is carried out at about 50 mm Hg and about 15° C. for 2 hours.
- the vacuum distillation procedure reduces the pre-crystallization levels of toluene or methylene chloride to less than 400 p.p.m.
- Other options to break up the emulsion and effect better phase separation are less effective; these include filtration of the crude aqueous phase through a bed of CeliteTM, increasing the settling time, and addition of a strong electrolyte.
- a C 1-3 -alkyl formate charge preferably methyl formate
- methyl formate is added over the first 30 minutes to bring the batch from a pH of about 13.5 to near supersaturation at a pH of about 10.6 to 10.8.
- the methyl formate addition is accomplished through a diptube which is narrowed at one end to create a fine stream and which is located near and perpendicular to the impeller tip. This technique ensures rapid dispersion of the methyl formate so that occlusion of impurities is minimized.
- Crude omeprazole at this stage contains less than 100 p.p.m. of residual toluene or methylene chloride, as determined by gas-liquid chromatographic analysis.
- the crude crystallized product is then filtered, washed with 0.01-1.0%, preferably 0.1%, ammonia-water, and then methanol.
- the crude wet omeprazole is then purified by dissolving it in 2:1-0.5-1 (v/v) methanol-water solution containing aqueous base, preferably 50% NaOH or KOH, at 20° C., cooling the basic solution to about 0-5° C., reducing the pH from >11.0 to approximately 10.5 by subsurface addition through a narrowed end diptube (configuration of apparatus same as in crude isolation step) of aqueous acetic acid, preferably 25% aqueous acetic acid, over a 30-minute period, while maintaining the temperature at 0-5° C.
- aqueous base preferably 50% NaOH or KOH
- the batch is seeded with pure omeprazole (100% by HPLC), and the subsurface addition of 25% aqueous acetic acid is continued over a 2-4 hour period until a pH of about 9.0 is attained.
- the batch is then aged for 0.5-1.0, preferably 0.5, hours. Following the aging period, the product is filtered, washed with the same methanol-water mixture to displace the mother liquors containing the impurities, and finally with cold methanol. Pure omeprazole is obtained after vacuum drying with a nitrogen purge at 30-50 mm Hg and 30-35° C.
- the optimal methanol-water ratio in this final purification step is 1:1. Previous methods used a higher methanol to water ratio. Lowering the proportion of methanol in the solvent mixture used in the displacement wash minimizes solubility losses and provides the purification demands, thereby improving the yield of the final product without compromising product quality.
- Crystalline omeprazole obtained using the improved process of the instant invention has an HPLC purity of 100% with no detectable levels of entrained residual toluene or methylene chloride from the crude step as measured by gas-liquid chromatography, the detection limit being 3 p.p.m.
- Prior methods have afforded omeprazole containing 30-100 p.p.m. of residual non-alcoholic organic reaction solvent, namely toluene or methylene chloride.
- the pure product contains less than 20 p.p.m. of residual methanol as the crystallization solvent.
- omeprazole prepared according to the process of the present invention may be mixed with a solid, pulverulent carrier, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives or gelatin, as well as an antifriction agent such as magnesium stearate, calcium stearate, and polyethyleneglycol waxes.
- a solid, pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives or gelatin
- an antifriction agent such as magnesium stearate, calcium stearate, and polyethyleneglycol waxes.
- the above-prepared core may be coated with a concentrated solution of sugar, which may contain gum arabic, gelatin, talc, titanium dioxide, or with a lacquer dissolved in volatile organic solvent or mixture of solvents.
- various dyes may be added in order to distinguish among tablets with
- Soft gelatin capsules may be prepared which contain a mixture of pure omeprazole prepared according to the process of the present invention and vegetable oil.
- Hard gelatin capsules may contain granules of the active compound in combination with a solid, pulverulent carrier, such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives, or gelatin.
- Pharmaceutical tablets for oral use are prepared in the following manner.
- the solid substances are ground or sieved to a certain particle size, and the binding agent is homogenized and suspended in a suitable solvent.
- the solid omeprazole prepared according to the process of the present invention and auxiliary agents are mixed with the binding agent solution.
- the resulting mixture is moistened to form a uniform suspension having the consistency of wet snow.
- the moistening causes the particles to aggregate slightly, and the resulting mass is pressed through a stainless steel sieve having a mesh size of about 1 millimeter.
- the layers of the mixture are dried in carefully controlled drying cabinets for approximately ten hours to obtain the desired particle size and consistency.
- the granules of the dried mixture are sieved to remove any powder.
- the mixture is pressed into tablets using a machine with the appropriate punches and dies to obtain the desired tablet size.
- the pressure applied affects the size of the tablet, its strength and ability to dissolve in water.
- the compression pressure used should be in the range of 0.5 to 5 tons.
- the tablets, especially those which are rough or bitter, may be coated with a layer of sugar or some other palatable substance. They are then packaged by machines having electronic counting devices.
- the HPLC system was equilibrated for at least 10 minutes at the mobile phase condition given in Step A.
- the standard preparation from Step C was injected twice, and the average area response for the 3-methylisoquinoline peaks should agree within ⁇ 1% of their average.
- the sample preparation was injected once.
- an MCPBA sample from Spectrum (Lot# LF0102, 72.7% MCPBA) was assayed, and a value of 72.8% (wt. %) for MCPBA was obtained.
- the solution is then cooled between 0-5° C. and added, subsurfacely directed at the tip of the impeller, to the rapidly agitated solution of pyrmetazole over a 2-hour period.
- the oxidation conversion was 99.8% with no over-oxidation to sulfone or N-oxides, as determined by HPLC analysis.
- Cold deionized water 115 mL, 5° C.
- 50% NaOH 15 mL
- the solution was allowed to stand at 0-5° C. for thirty minutes and the phases separated.
- the methylene chloride layer was discarded and the aqueous layer concentrated under vacuum (50 mm Hg) for 2 hours at 15° C. to remove the bulk of the residual methylene chloride.
- the ethanol level was then re-adjusted to 15% v/v. At this point the residual methylene chloride level was less than 200 p.p.m., as determined by gas-liquid chromatographic analysis.
- the crude product was then isolated by reactive crystallization by subsurface addition of methyl formate. Approximately 40% of the methyl formate charge (approximately 6 mL) was added during the first thirty minutes to adjust the pH from about 13.5 to 10.8. The mixture was allowed to stand for about twenty minutes to allow the internal temperature to cool back down to approximately 20° C. The mixture was seeded with pure omeprazole (0.5 g), and the remainder of the methyl formate (approximately 9 mL) was added subsurfacely over a 7-hour period to a pH of 9.0. The crude product was filtered, washed with 0.1% ammonia-water (50 mL) followed by methanol (40 mL).
- the crude product was dissolved in 1:1 methanol-water (270 mL) and 50% NaOH (4 mL) in a 500-mL, three-necked, round-bottomed flask at 20° C. The solution was then cooled to 0-5° C. and the pH adjusted from >11.0 to approximately 10.5 by subsurface addition of 25% acetic acid over a 30-minute period, maintaining the temperature at 5° C. The batch was seeded with pure omeprazole (0.5 g), and the subsurface addition of 25% acetic acid was continued over a 4-hour period until pH 9.0 was achieved.
- the oxidation conversion was 99.8% with no over-oxidation to sulfone or N-oxides.
- Cold deionized water 145 mL, 5° C.
- 50% NaOH (12 mL) were then added to the reaction mixture.
- the solution was allowed to stand at 0-5° C. for thirty minutes and the phases separated.
- the toluene layer was discarded and the aqueous layer concentrated under vacuum (50 mm Hg) for 2 hours at 15° C. to remove the bulk of the residual toluene.
- the ethanol level was then adjusted to 15% v/v. At this point the residual toluene level was less than 400 p.p.m., as determined by gas-liquid chromatographic analysis.
- Example 2 The crude product was then isolated by reactive crystallization by subsurface addition of methyl formate as in Example 2. It was filtered, washed with 0.1% ammonia-water (50 mL) followed by methanol (40 mL). The wet crude product was then processed to pure omeprazole as in Example 2. The overall yield was 93.8% with an HPLC purity of 100%. The residual methanol level was 10 ppm, as determined by gas-liquid chromatography, with no detectable levels of toluene (detection limit 3 p.p.m).
- a pharmaceutical composition containing omeprazole prepared according to the process of the present invention as the active ingredient is illustrated in the following formulation.
- Capsules containing 30 mg of omeprazole of the present invention were prepared from the following ingredients:
- the omeprazole of Example 2 or 3 was mixed with the dry ingredients and granulated with a solution of disodium hydrogenphosphate. The wet mass was forced through an extruder and sphreronized and dried in a fluidized bed dryer.
- the final coated pellets were filled into capsules.
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Abstract
Description
______________________________________ Step B. Reagents ______________________________________ Acetonitrile (MeCN): HPLC Grade Water: HPLC Grade Phosphoric Acid: HPLC Grade 3-Methylisoquinoline: 98% Sample Diluent: 50/50 (MeCN/0.1% H.sub.3 PO.sub.4) ______________________________________
______________________________________ Compound of Example 2 or 3 300 grams Lactose 700 grams Microcrystalline cellulose 40 grams Hydroxypropyl cellulose, low substituted 62 grams Disodium hydrogenphosphate 2 grams Purified water q.s. ______________________________________
______________________________________ Coating solution: ______________________________________ Hydroxypropyl methylcellulose phthalate 70 grams Cetyl alcohol 4 grams Acetone 200 grams Ethanol 600 grams ______________________________________
Claims (8)
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US09/387,945 US6147103A (en) | 1998-08-11 | 1999-09-01 | Omeprazole process and compositions thereof |
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US9603798P | 1998-08-11 | 1998-08-11 | |
US09/169,231 US6166213A (en) | 1998-08-11 | 1998-10-09 | Omeprazole process and compositions thereof |
US09/387,945 US6147103A (en) | 1998-08-11 | 1999-09-01 | Omeprazole process and compositions thereof |
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US09/387,945 Expired - Lifetime US6147103A (en) | 1998-08-11 | 1999-09-01 | Omeprazole process and compositions thereof |
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IL (2) | IL141324A0 (en) |
NO (1) | NO321054B1 (en) |
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Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4255431A (en) * | 1978-04-14 | 1981-03-10 | Aktiebolaget Hassle | Gastric acid secretion inhibiting substituted 2-(2-benzimidazolyl)-pyridines, pharmaceutical preparations containing same, and method for inhibiting gastric acid secretion |
GB2239453A (en) * | 1989-11-27 | 1991-07-03 | Haessle Ab | Omeprazole |
EP0484265A1 (en) * | 1990-10-31 | 1992-05-06 | Centro Genesis Para La Investigacion, S.L. | A process for the preparation of omeprazol |
EP0302720B1 (en) * | 1987-08-04 | 1992-11-11 | Takeda Chemical Industries, Ltd. | Production of 2-(2-pyridylmethylsulfinyl)-benzimidazole compounds |
US5386032A (en) * | 1990-06-07 | 1995-01-31 | Aktiebolaget Astra | Method of synthesis of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl-1H-benzimidazole (omeprazole) |
US5391752A (en) * | 1991-09-20 | 1995-02-21 | Merck & Co., Inc. | Process for the preparation of antiulcer agents |
WO1996038175A1 (en) * | 1995-06-02 | 1996-12-05 | Takeda Chemical Industries, Ltd. | Stabilized composition comprising an antiulcerative benzimidazole |
WO1998009962A1 (en) * | 1996-09-09 | 1998-03-12 | Slovakofarma, A.S. | Method of omeprazole preparation |
WO1998040378A1 (en) * | 1997-03-07 | 1998-09-17 | A/S Gea Farmaceutisk Fabrik | Process for the preparation of 2-[[(2-pyridinyl)methyl]sulfinyl]-1h-benzimidazoles and novel compounds of use for such purpose |
WO1998040377A1 (en) * | 1997-03-07 | 1998-09-17 | A/S Gea Farmaceutisk Fabrik | Process for the preparation of 2-[[(2-pyridinyl)methyl]sulfinyl]-1h-benzimidazoles and novel compounds of use for such purpose |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE416649B (en) * | 1974-05-16 | 1981-01-26 | Haessle Ab | PROCEDURE FOR THE PREPARATION OF SUBSTANCES WHICH PREVENT Gastric acid secretion |
JPH0643426B2 (en) * | 1986-07-25 | 1994-06-08 | 東京田辺製薬株式会社 | Imidazo [4,5-b] pyridine derivative, method for producing the same, and antiulcer agent containing the same |
TW359614B (en) * | 1993-08-31 | 1999-06-01 | Takeda Chemical Industries Ltd | Composition containing benzimidazole compounds for rectal administration |
SE521100C2 (en) * | 1995-12-15 | 2003-09-30 | Astra Ab | Process for the preparation of a benzimidazole compound |
-
1998
- 1998-10-09 US US09/169,231 patent/US6166213A/en not_active Expired - Lifetime
-
1999
- 1999-08-06 PT PT99940964T patent/PT1104417E/en unknown
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- 1999-09-01 US US09/387,945 patent/US6147103A/en not_active Expired - Lifetime
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- 2001-02-07 IL IL141324A patent/IL141324A/en not_active IP Right Cessation
- 2001-02-09 NO NO20010677A patent/NO321054B1/en unknown
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Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4255431A (en) * | 1978-04-14 | 1981-03-10 | Aktiebolaget Hassle | Gastric acid secretion inhibiting substituted 2-(2-benzimidazolyl)-pyridines, pharmaceutical preparations containing same, and method for inhibiting gastric acid secretion |
EP0302720B1 (en) * | 1987-08-04 | 1992-11-11 | Takeda Chemical Industries, Ltd. | Production of 2-(2-pyridylmethylsulfinyl)-benzimidazole compounds |
GB2239453A (en) * | 1989-11-27 | 1991-07-03 | Haessle Ab | Omeprazole |
US5386032A (en) * | 1990-06-07 | 1995-01-31 | Aktiebolaget Astra | Method of synthesis of 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl-1H-benzimidazole (omeprazole) |
EP0484265A1 (en) * | 1990-10-31 | 1992-05-06 | Centro Genesis Para La Investigacion, S.L. | A process for the preparation of omeprazol |
US5391752A (en) * | 1991-09-20 | 1995-02-21 | Merck & Co., Inc. | Process for the preparation of antiulcer agents |
WO1996038175A1 (en) * | 1995-06-02 | 1996-12-05 | Takeda Chemical Industries, Ltd. | Stabilized composition comprising an antiulcerative benzimidazole |
WO1998009962A1 (en) * | 1996-09-09 | 1998-03-12 | Slovakofarma, A.S. | Method of omeprazole preparation |
WO1998040378A1 (en) * | 1997-03-07 | 1998-09-17 | A/S Gea Farmaceutisk Fabrik | Process for the preparation of 2-[[(2-pyridinyl)methyl]sulfinyl]-1h-benzimidazoles and novel compounds of use for such purpose |
WO1998040377A1 (en) * | 1997-03-07 | 1998-09-17 | A/S Gea Farmaceutisk Fabrik | Process for the preparation of 2-[[(2-pyridinyl)methyl]sulfinyl]-1h-benzimidazoles and novel compounds of use for such purpose |
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Also Published As
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KR20010072382A (en) | 2001-07-31 |
IL141324A0 (en) | 2002-03-10 |
NZ509798A (en) | 2003-06-30 |
CA2338967A1 (en) | 2000-02-24 |
DE69935915T2 (en) | 2008-01-10 |
BR9912883A (en) | 2001-09-25 |
CN1227246C (en) | 2005-11-16 |
US6166213A (en) | 2000-12-26 |
ZA200101140B (en) | 2002-04-09 |
DK1104417T3 (en) | 2007-07-16 |
WO2000009497A1 (en) | 2000-02-24 |
NO20010677L (en) | 2001-04-09 |
AU764642B2 (en) | 2003-08-28 |
NO321054B1 (en) | 2006-03-06 |
EP1104417A1 (en) | 2001-06-06 |
AU5470999A (en) | 2000-03-06 |
NO20010677D0 (en) | 2001-02-09 |
KR100632725B1 (en) | 2006-10-16 |
DE69935915D1 (en) | 2007-06-06 |
CN1322201A (en) | 2001-11-14 |
EP1104417A4 (en) | 2002-12-18 |
PT1104417E (en) | 2007-06-29 |
IL141324A (en) | 2007-05-15 |
ATE360626T1 (en) | 2007-05-15 |
ES2285857T3 (en) | 2007-11-16 |
JP2002522537A (en) | 2002-07-23 |
EP1104417B1 (en) | 2007-04-25 |
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